Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2003 Feb;62(2):120–126. doi: 10.1136/ard.62.2.120

Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage

O Meyer 1, C Labarre 1, M Dougados 1, P Goupille 1, A Cantagrel 1, A Dubois 1, P Nicaise-Roland 1, J Sibilia 1, B Combe 1
PMCID: PMC1754441  PMID: 12525380

Abstract

Objective: To study the value of antibodies to citrullinated proteins/peptides for predicting joint outcomes in patients with recent onset rheumatoid arthritis (RA).

Methods: 191 patients with RA onset within the past year were followed up prospectively for five years. Serum samples obtained from 145 patients at baseline before disease modifying antirheumatic drug treatment were examined using three anticitrullinated protein/peptide antibody assays: antiperinuclear factor (APF) by indirect immunofluorescence (IIF), antikeratin antibodies (AKA) by IIF, and anti-cyclic citrullinated peptide (CCP) antibodies by enzyme linked immunosorbent assay (ELISA). Radiographs of the hands and feet taken at baseline and after three and five years were evaluated using Sharp scores modified by van der Heijde.

Results:Anti-CCP ELISA was positive in 58.9% of patients. APF/anti-CCP agreement was 77%. The likelihood of a total Sharp score increase after five years was significantly greater among patients with anti-CCP antibodies (67%; odds ratio (OR) 2.5; 95% confidence interval (95% CI) 1.2 to 5.0) or APF (57%; OR 2.4; 95% CI 1.2 to 4.9) but not rheumatoid factor (RF; OR 0.7; 95% CI 0.3 to 1.5). Mean values for radiographic damage, erosion, and joint narrowing scores at the three times were significantly higher in patients with anti-CCP or APF than in those without. AKA did not significantly predict radiographic damage. In separate analyses of patients with and without RF, anti-CCP or APF was better than RF for predicting total joint damage and joint damage progression after five years.

Conclusion: Antibodies to citrullinated proteins/peptides determined early in the course of RA by APF IIF or anti-CCP ELISA are good predictors of radiographic joint damage. Further studies of clinical, laboratory, and genetic parameters are needed to improve RA outcome prediction in clinical practice.

Full Text

The Full Text of this article is available as a PDF (230.7 KB).

Figure 1.

Figure 1

Open in a new tab

Mean (absolute) Sharp scores in patients with or without (A) anti-CCP ELISA antibodies or (B) APF antibodies, at baseline.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aho K., von Essen R., Kurki P., Palosuo T., Heliövaara M. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process. J Rheumatol. 1993 Aug;20(8):1278–1281. [PubMed] [Google Scholar]
  2. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  3. Bas S., Perneger T. V., Mikhnevitch E., Seitz M., Tiercy J. M., Roux-Lombard P., Guerne P. A. Association of rheumatoid factors and anti-filaggrin antibodies with severity of erosions in rheumatoid arthritis. Rheumatology (Oxford) 2000 Oct;39(10):1082–1088. doi: 10.1093/rheumatology/39.10.1082. [DOI] [PubMed] [Google Scholar]
  4. Berthelot J. M., Maugars Y., Castagné A., Audrain M., Prost A. Antiperinuclear factors are present in polyarthritis before ACR criteria for rheumatoid arthritis are fulfilled. Ann Rheum Dis. 1997 Feb;56(2):123–125. doi: 10.1136/ard.56.2.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Combe B., Dougados M., Goupille P., Cantagrel A., Eliaou J. F., Sibilia J., Meyer O., Sany J., Daurès J. P., Dubois A. Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study. Arthritis Rheum. 2001 Aug;44(8):1736–1743. doi: 10.1002/1529-0131(200108)44:8<1736::AID-ART308>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  6. Combe B., Eliaou J. F., Daurès J. P., Meyer O., Clot J., Sany J. Prognostic factors in rheumatoid arthritis. Comparative study of two subsets of patients according to severity of articular damage. Br J Rheumatol. 1995 Jun;34(6):529–534. doi: 10.1093/rheumatology/34.6.529. [DOI] [PubMed] [Google Scholar]
  7. Cordonnier C., Meyer O., Palazzo E., de Bandt M., Elias A., Nicaise P., Haïm T., Kahn M. F., Chatellier G. Diagnostic value of anti-RA33 antibody, antikeratin antibody, antiperinuclear factor and antinuclear antibody in early rheumatoid arthritis: comparison with rheumatoid factor. Br J Rheumatol. 1996 Jul;35(7):620–624. doi: 10.1093/rheumatology/35.7.620. [DOI] [PubMed] [Google Scholar]
  8. Drossaers-Bakker K. W., Amesz E., Zwinderman A. H., Breedveld F. C., Hazes J. M. A comparison of three radiologic scoring systems for the long-term assessment of rheumatoid arthritis: findings of an ongoing prospective inception cohort study of 132 women followed up for a median of twelve years. Arthritis Rheum. 2000 Jul;43(7):1465–1472. doi: 10.1002/1529-0131(200007)43:7<1465::AID-ANR8>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  9. Feigenbaum S. L., Masi A. T., Kaplan S. B. Prognosis in rheumatoid arthritis. A longitudinal study of newly diagnosed younger adult patients. Am J Med. 1979 Mar;66(3):377–384. doi: 10.1016/0002-9343(79)91055-6. [DOI] [PubMed] [Google Scholar]
  10. Forslind K., Vincent C., Serre G., Svensson B. Antifilaggrin autoantibodies in early rheumatoid arthritis. Scand J Rheumatol. 2000;29(5):320–322. doi: 10.1080/030097400447714. [DOI] [PubMed] [Google Scholar]
  11. Girbal-Neuhauser E., Durieux J. J., Arnaud M., Dalbon P., Sebbag M., Vincent C., Simon M., Senshu T., Masson-Bessière C., Jolivet-Reynaud C. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol. 1999 Jan 1;162(1):585–594. [PubMed] [Google Scholar]
  12. Goldbach-Mansky R., Lee J., McCoy A., Hoxworth J., Yarboro C., Smolen J. S., Steiner G., Rosen A., Zhang C., Ménard H. A. Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res. 2000 Mar 31;2(3):236–243. doi: 10.1186/ar93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hulsmans H. M., Jacobs J. W., van der Heijde D. M., van Albada-Kuipers G. A., Schenk Y., Bijlsma J. W. The course of radiologic damage during the first six years of rheumatoid arthritis. Arthritis Rheum. 2000 Sep;43(9):1927–1940. doi: 10.1002/1529-0131(200009)43:9<1927::AID-ANR3>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  14. Janssens X., Veys E. M., Verbruggen G., Declercq L. The diagnostic significance of the antiperinuclear factor for rheumatoid arthritis. J Rheumatol. 1988 Sep;15(9):1346–1350. [PubMed] [Google Scholar]
  15. Kaarela K. Prognostic factors and diagnostic criteria in early rheumatoid arthritis. Scand J Rheumatol Suppl. 1985;57:1–54. doi: 10.3109/03009748509104317. [DOI] [PubMed] [Google Scholar]
  16. Kroot E. J., de Jong B. A., van Leeuwen M. A., Swinkels H., van den Hoogen F. H., van't Hof M., van de Putte L. B., van Rijswijk M. H., van Venrooij W. J., van Riel P. L. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2000 Aug;43(8):1831–1835. doi: 10.1002/1529-0131(200008)43:8<1831::AID-ANR19>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
  17. Lassere M., Boers M., van der Heijde D., Boonen A., Edmonds J., Saudan A., Verhoeven A. C. Smallest detectable difference in radiological progression. J Rheumatol. 1999 Mar;26(3):731–739. [PubMed] [Google Scholar]
  18. Masson-Bessière C., Sebbag M., Girbal-Neuhauser E., Nogueira L., Vincent C., Senshu T., Serre G. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol. 2001 Mar 15;166(6):4177–4184. doi: 10.4049/jimmunol.166.6.4177. [DOI] [PubMed] [Google Scholar]
  19. Meyer O., Tauxe F., Fabregas D., Gabay C., Goycochea M., Haim T., Elias A., Kahn M. F. Anti-RA 33 antinuclear autoantibody in rheumatoid arthritis and mixed connective tissue disease: comparison with antikeratin and antiperinuclear antibodies. Clin Exp Rheumatol. 1993 Sep-Oct;11(5):473–478. [PubMed] [Google Scholar]
  20. Muñoz-Fernández S., Alvarez-Doforno R., González-Tarrio J. M., Balsa A., Richi P., Fontán G., Gijón-Baños J., Martin-Mola E. Antiperinuclear factor as a prognostic marker in rheumatoid arthritis. J Rheumatol. 1999 Dec;26(12):2572–2577. [PubMed] [Google Scholar]
  21. Ménard H. A., Lapointe E., Rochdi M. D., Zhou Z. J. Insights into rheumatoid arthritis derived from the Sa immune system. Arthritis Res. 2000 Aug 17;2(6):429–432. doi: 10.1186/ar122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Möttönen T., Hannonen P., Jokinen I., Arvilommi M., Oka M. Relation between bone erosions and rheumatoid factor IgA and IgM isotypes in recent onset rheumatoid arthritis. Scand J Rheumatol Suppl. 1988;75:244–249. doi: 10.3109/03009748809096771. [DOI] [PubMed] [Google Scholar]
  23. Möttönen T., Paimela L., Leirisalo-Repo M., Kautiainen H., Ilonen J., Hannonen P. Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with "sawtooth" strategy. Ann Rheum Dis. 1998 Sep;57(9):533–539. doi: 10.1136/ard.57.9.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. NIENHUIS R. L., MANDEMA E. A NEW SERUM FACTOR IN PATIENTS WITH RHEUMATOID ARTHRITIS; THE ANTIPERINUCLEAR FACTOR. Ann Rheum Dis. 1964 Jul;23:302–305. doi: 10.1136/ard.23.4.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Paimela L., Gripenberg M., Kurki P., Leirisalo-Repo M. Antikeratin antibodies: diagnostic and prognostic markers for early rheumatoid arthritis. Ann Rheum Dis. 1992 Jun;51(6):743–746. doi: 10.1136/ard.51.6.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Paimela L., Palosuo T., Aho K., Lukka M., Kurki P., Leirisalo-Repo M., von Essen R. Association of autoantibodies to filaggrin with an active disease in early rheumatoid arthritis. Ann Rheum Dis. 2001 Jan;60(1):32–35. doi: 10.1136/ard.60.1.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schellekens G. A., Visser H., de Jong B. A., van den Hoogen F. H., Hazes J. M., Breedveld F. C., van Venrooij W. J. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000 Jan;43(1):155–163. doi: 10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  28. Schellekens G. A., de Jong B. A., van den Hoogen F. H., van de Putte L. B., van Venrooij W. J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998 Jan 1;101(1):273–281. doi: 10.1172/JCI1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Westgeest A. A., Boerbooms A. M., Jongmans M., Vandenbroucke J. P., Vierwinden G., van de Putte L. B. Antiperinuclear factor: indicator of more severe disease in seronegative rheumatoid arthritis. J Rheumatol. 1987 Oct;14(5):893–897. [PubMed] [Google Scholar]
  30. Young A., Corbett M., Winfield J., Jaqueremada D., Williams P., Papasavvas G., Hay F., Roitt I. A prognostic index for erosive changes in the hands, feet, and cervical spines in early rheumatoid arthritis. Br J Rheumatol. 1988 Apr;27(2):94–101. doi: 10.1093/rheumatology/27.2.94. [DOI] [PubMed] [Google Scholar]
  31. Young B. J., Mallya R. K., Leslie R. D., Clark C. J., Hamblin T. J. Anti-keratin antibodies in rheumatoid arthritis. Br Med J. 1979 Jul 14;2(6182):97–99. doi: 10.1136/bmj.2.6182.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. van Jaarsveld C. H., ter Borg E. J., Jacobs J. W., Schellekens G. A., Gmelig-Meyling F. H., van Booma-Frankfort C., de Jong B. A., van Venrooij W. J., Bijlsma J. W. The prognostic value of the antiperinuclear factor, anti-citrullinated peptide antibodies and rheumatoid factor in early rheumatoid arthritis. Clin Exp Rheumatol. 1999 Nov-Dec;17(6):689–697. [PubMed] [Google Scholar]
  33. van Zeben D., Breedveld F. C. Prognostic factors in rheumatoid arthritis. J Rheumatol Suppl. 1996 Mar;44:31–33. [PubMed] [Google Scholar]
  34. van Zeben D., Hazes J. M., Zwinderman A. H., Cats A., van der Voort E. A., Breedveld F. C. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study. Ann Rheum Dis. 1992 Sep;51(9):1029–1035. doi: 10.1136/ard.51.9.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. van Zeben D., Hazes J. M., Zwinderman A. H., Vandenbroucke J. P., Breedveld F. C. Factors predicting outcome of rheumatoid arthritis: results of a followup study. J Rheumatol. 1993 Aug;20(8):1288–1296. [PubMed] [Google Scholar]
  36. van der Heide A., Remme C. A., Hofman D. M., Jacobs J. W., Bijlsma J. W. Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis. Arthritis Rheum. 1995 Oct;38(10):1466–1474. doi: 10.1002/art.1780381013. [DOI] [PubMed] [Google Scholar]
  37. van der Heijde D. M., van Riel P. L., Nuver-Zwart I. H., Gribnau F. W., vad de Putte L. B. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet. 1989 May 13;1(8646):1036–1038. doi: 10.1016/s0140-6736(89)92442-2. [DOI] [PubMed] [Google Scholar]
  38. van der Heijde D. M., van Riel P. L., van Leeuwen M. A., van 't Hof M. A., van Rijswijk M. H., van de Putte L. B. Prognostic factors for radiographic damage and physical disability in early rheumatoid arthritis. A prospective follow-up study of 147 patients. Br J Rheumatol. 1992 Aug;31(8):519–525. doi: 10.1093/rheumatology/31.8.519. [DOI] [PubMed] [Google Scholar]
  39. von Essen R., Kurki P., Isomäki H., Okubo S., Kautiainen H., Aho K. Prospect for an additional laboratory criterion for rheumatoid arthritis. Scand J Rheumatol. 1993;22(6):267–272. doi: 10.3109/03009749309095137. [DOI] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES